Heteroaromatic oxidation pyridine

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

Fluoropyridines form valuable starting materials for a range of disubstituted pyridines because, after lithiation, nucleophilic substitution of fluoride (sometimes via the N-oxide) can be used to introduce, say, N or O substituents as in 191 and 192 (Scheme 96). Subsequent annelations can allow complex polycyclic heteroaromatics to be constructed. ... 

Reaction with oxygen nucleophiles provides a simple route for the oxidation (Fig. 88) [229] and alkoxylation [230] (Fig. 89) of pyridine and related heteroaromatics. 

Recently37, the importance of CT complexes in the chemistry of heteroaromatic N-oxides has been investigated in nucleophilic aromatic substitutions. Electron acceptors (tetracyanoethylene and p-benzoquinones) enhance the electrophilic ability of pyridine-N-oxide (and of quinoline-N-oxide) derivatives by forming donor-acceptor complexes which facilitate the reactions of nucleophiles on heteroaromatic substrates. 

Sulfotransferase activity is not restricted to minoxidil. The ability of other pyrimidine-, as well as pyridine-, triazine- and imidazole N-oxides to serve as substrates was investigated using soluble liver preparation and PAPS. The variety of structures studied indicated that heteroaromatic N-oxides are generally metabolized by sulfotransferases183. Presumably, all of the heterocycles tested were conjugated via their N-oxide oxygens. 

Heteroaromatic amines can oxidize to the corresponding N-oxide, which are typically stable enough to be isolated and detected as degradation products. The N-oxide functionality typically increases the reactivity of the aromatic ring. For example, the N-oxide functionality in pyridine N-oxide facilitates both electrophilic and nucleophilic substitution at the alpha and gamma positions (57). 

A DFT study of the molecular orbitals of pyridine and a number of heteroaromatics unreactive to electrophilic substitution shows that the HOMOs of these compounds are not r-orbitals and so their low reactivity can be explained by assuming frontier orbital control of their substitution reactions.1 Consistent with this rationalization is the fact that in the case of pyridine-A-oxide and a number of other reactive substrates the HOMOs are n-orbitals. 4,6-Dinitrobenzofuroxan (1) is a superelectrophile and reacts with some supernucleophilic l,3,5-tris(A,A-dialkylamino)benzenes to form the first observed Meisenheimer-Wheland zwitterionic complexes [e.g. (2)].2... 

V-Oxides of heteroaromatic compounds are generally electrolytic-ally reducible in acid solution242-254 the most studied compounds of this type are the pyridine A-oxides.242 249, 250 At low pH pyridine A-oxide gives a two-electron polarographic wave, but at pH > 4 the wave height diminishes, as the preprotonation step becomes too slow [Eq. (9)]. 

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